The present invention relates to the field of antipsychotic drugs, in particular to polycondensated heterocycles with a pyrrolo[2,1-b][1,3]benzothiazepine structure.
The intervention of dopamine and dopaminergic neurons in the pathology of a variety of psychiatric and neurological disorders has been amply documented (Caine, D. B., Therapeutics and Neurology; Blackwell Scientific Publications, Oxford 1980, p. 281). In addition, it is also known that drugs which are active on dopamine receptors may play an important role in the therapy of such disorders; there is therefore considerable interest in the effects of dopamine agonist and antagonist compounds on dopaminergic receptors, particularly with a view to their therapeutic implications.
Chlorpromazine and aloperidol have long been the treatment of choice for acute and chronic schizophrenia. It has been postulated that these drugs relieve the positive symptoms of the disease by blocking dopaminergic transmission in certain areas of the brain. Chlorpromazine and aloperidol are defined as xe2x80x9ctypical neuroleptic agentsxe2x80x9d: their action is characterised by remission of the symptoms of schizophrenia, accompanied, however, by unwanted extrapyramidal collateral symptoms (motor disorders, catalepsy, hyperprolactinaemia, etc.). The elimination of these adverse effects therefore constitutes an important objective in the development of new neuroleptic therapies.
Clinical trials have demonstrated that not only dopamine antagonists but also 5-HT2 antagonist compounds are capable of improving the symptoms of schizophrenia, in particular, it has been observed that the co-administration of 5-HT2 antagonists and xe2x80x9ctypicalxe2x80x9d antipsychotic agents reduces the incidence of extapyramridal symptoms as compared to treatment with neuroleptic agents alone (Psychopharmacol., 99, 1989, S18-S27; Niemegeers et al. in 5-HT2 Receptor Antagonists in Schizophrenia, Racagni Ed., Elsevier Publishers, 1991, Vol. 1, pp. 535-537).
Further developments in this sense have led to the generation of drugs with a mixed antagonist component, i.e. which are active on different receptors.
Clozapine (8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine) is an antipsychotic agent capable of simultaneously antagonising dopamine on D2 receptors and serotonin on 5-HT2 receptors. This new action profile, called xe2x80x9catypicalxe2x80x9d, allows schizophrenia to be treated with a lower incidence of extrapyramidal symptoms (J. Med. Chem., 39, 1996, pp. 1172-1188).
Unfortunately, the occurrence of cases of agranulocytosis has limited the therapeutic use of this drug (Lancet. 1975, 2, 657).
Octoclothepin (8-chloro-10-(4-methylpiperazino)-10,11-dihydrodibenzo[b,f]thiepin) is a compound partly endowed with xe2x80x9catypicalxe2x80x9d activity. Its pharmacological activity has been studied in relation to the optical isomers of this compound (J. Med. Chem., 1991, 34, 2023-2030): a slightly greater effect on schizophrenia by the (S) form is unfortunately associated with a greater incidence of extrapyramidal effects, so that its use has been withdrawn from clinical trials. The (R) isomer presents a more xe2x80x9catypicalxe2x80x9d profile, with fewer side effects, but also an inferior general potency. Moreover, the two isomers prove to be endowed with the same activity as 5-HT2 and D1 antagonists.
In view of the studies cited above, the need for antipsychotic agents with substantial therapeutic activity and without side effects remains unsatisfied. In particular, the search continues for antipsychotic agents which present greater neuroleptic activity and a lower incidence of extapyramidal effects.
It has now surprisingly been found that polycondensated heterocycles with a pyrrolo[2,1-b][1,3]benzothiazepine are endowed with an interesting pharmacological profile as antipsychotic activity.
The present invention describes polycondensated heterocycles with a pyrrolo[2,1-b][1,3]benzothiazepine structure. As compared to known antipsychotic agents, the compounds according to the invention present substantial activity associated with a simultaneous reduction in unwanted extrapyramidal symptoms. The compounds object of the invention described herein can be formulated in pharmaceutical compositions for the treatment of psychoses such as, for example, schizophrenia.
Accordingly, it is an object of the present invention polycondensated heterocycles with a pyrrolo[2,1-b][1,3]benzothiazepine structure as disclosed in the formula (I) below.
Another object of the present invention is a process for the preparation of said compounds.
Still another object of the present invention is the use of said compounds as medicaments, in particular as antipsychotic agents, for the treatment of psychosis, such as schizophrenia, paranoid states, manic-depressive states, affective disorders, social withdrawal, personality regression, or hallucinations.
In its industrial aspects, the present invention provides pharmaceutical compositions comprising at least a compound of the invention.
The invention described herein relates to new derivatives with a neuroleptic action, corresponding to the following structural formula (I): 
where:
R=H, Cl, Br, F, I, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl, C5-C6 cycloalkyl;
R1=dialkylamine, 4-alkyl-1-piperazinyl, 4-hydroxyalkyl-1-piperazinyl, 1-imidazolyl, 4-alkyl-1-piperidinyl
R2=hydrogen, C1-C4 alkoxy, C1-C4 alkylthio;
and the pharmaceutically acceptable salts thereof.
The formula (I) derivatives possess a chiral carbon atom in position 9 on the benzothiazepine ring. The invention described herein comprises both the formula (I) derivative in racemic form and the single (R) and (S) isomers, separately.
In formula (I), R preferably represents bromine, chlorine, fluorine or hydrogen, more preferably chlorine or fluorine; R1 preferably a 4-methylpiperazinyl group; and R2 preferably hydrogen.
Preferred derivatives according to the invention are the products:
(xc2x1)-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine, hereinafter referred to as (xc2x1)-3a;
(xc2x1)-7-chloro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine, hereinafter referred to as (xc2x1)-3b (ST1455);
(+)-7-chloro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine, particularly preferred, hereinafter referred to as (+)-3b (ST1460)
(xc2x1)-7-fluoro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine, hereinafter referred to as (3c) (ST1456);
(xc2x1)-7-fluoro-9-(4-ethylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine (4c) (ST1457);
(xc2x1)-7-fluoro-9-[4-(2xe2x80x2-hyroxyethylpiperazin-1-yl]-9,10-dihydropyrrolo[2,1b][1,3]benzothiazepine (5c) (ST1458);
The invention described herein also relates to new, effective methods of synthesis to obtain the new pyrrolo[2,1-b][1,3]benzothiazepine structures. One of the problems encountered was that of realising a cyclisation method that made it possible to obtain the particular formula (I) tricyclic system with high yields.
The various synthesis methods described herein include a cyclisation reaction of a derivative comprising a phenyl group and a pyrrole group, where the cyclisation leads to the formation of a [1,3] thiazepine ring. The result of said cyclisation reaction is preferably a pyrrolobenzothiazepinone, which can be transformed into a formula (I) derivative by substituting the keto group on the thiazepine ring with a group selected from the definitions given above for the radical R1.
A process for the synthesis of formula (I) products is illustrated in Scheme 1A in its essential steps, and in Scheme 1B in detail. 
With reference to Scheme 1B, the process involves the reaction of 2-thiocyanate-pyrrole (11) with phenyl magnesium bromide to form thioether (12). Thioether (12), subjected to esterification and transacylation reactions, gives rise to the derivative methylselenolate (15) comprising a phenyl group and a pyrrole group. Derivative (15) is then subjected to a cyclisation reaction, with formation of product (9a) (pyrrolobenzothiazepinone). The cyclisation reaction is conducted in the presence of a crystalline complex of triflate copper (I) and benzene.
Lastly, product (9a) is transformed into a formula (I) derivative by means of subsequent modifications of the keto group on the thiazepine ring to obtain derivatives with R1 as described above.
One preferred process for the synthesis of formula (I) products is illustrated in Scheme 2A in its essential steps and in Schemes 2B in detail. 
With reference to Schemes 2B/1 and 2B/2, the process involves the formation of the intermediate product (21a,b,c, SCHEME 2B/1; bromophenylethanone; 21a: R=H; 21b: R=Cl; 21c=F). As far as the intermediate compound 21d is concerned, the synthetic path is outlined in the Scheme C below.
The intermediate product (21a,b,c,d) is transformed into the corresponding sulphoxide (23a,b,c,d). The latter, when subjected to a cyclisation reaction, leads to the formation of the product (9a,b,c,d) (pyrrolobenzothiapinone). The cyclisation reaction is conducted in the presence of trifluoracetic anhydride and dimethylformamide.
This second synthesis method is preferred in that the cyclisation reaction and consequent formation of the thiazepine ring occur with distinctly greater yields.
Products (9a), (9b), (9c) and (9d), obtained with the different synthesis methods described above are then transformed into a formula (I) derivative by substituting the keto group with a group selected from the definitions given above for the radical R1. 
It is then always possible to resolve the racemic products, however they are obtained, into the two active isomers by means of fractionated crystallisation of the diastereoisomeric salts obtained by salification with an optically active acid, such as tartaric acid, dibenzoyltartaric acid, camphoric acid, or camphor-sulphonic acid.
A detailed description of the above-mentioned synthesis methods is presented in the experimental part.
A further subject of the invention described herein consists in pharmaceutical compositions comprising formula (I) derivatives in combination with pharmacologically acceptable excipients and vehicles and optionally with additional active ingredients which are useful in the treatment of psychoses.
Examples of such optional active ingredients are the phenothiazines (e.g. chlorpromazine), the thiaxanthenes (e.g. chlorprothixene, titothixene), the butyrophenones (e.g. aloperidol), the dihydroindolones (e.g. molindone), the dibenzoxazepines (e.g. loxapine), the Rauwolfia alkaloids, etc.
Formula (I) compounds can be formulated in solid, liquid or semisolid pharmaceutical forms. Examples of liquid formulations are injectable solutions or solutions for oral use, syrups, elixirs, suspensions and emulsions. Examples of solid forms are tablets, capsules, microcapsules, powders and granulates.
Formula (I) compounds are endowed with a pronounced neuroleptic and antipsychotic activity. This enables them to be used in the prevention and treatment of psychoses such as schizophrenia, paranoid states, manic-depressive states, affective disorders, social withdrawal, personality regression, hallucinations, appetite disorders (anorexia) and related disorders. Additional indications may be analgesia/anaesthesia, neuroleptic anaesthesia, anxiety manifestations in the elderly, and extrapyramidal disturbances. The invention described herein therefore includes the use of formula (I) products in the preparation of medicinal products which are useful for the prevention and treatment of said disorders.
Some of the formula (I) products have an interesting D3:D1 ratio, indicating them useful in the treatment of the negative symptoms of schizophrenia involving the emotional and cognitive spheres such as, for instance, dementia.
As documented in the experimental part, the xe2x80x9catypicityxe2x80x9d of the neuroleptic action of formula (I) derivatives makes it possible to treat the above-mentioned pathologies effectively, at the same time reducing to a minimum the extrapyramidal side effects normally associated with the classic antipsychotic agents. The substantial receptor activity that characterises these compounds also makes it possible to considerably reduce the dose necessary to achieve a therapeutic response, thus reducing toxicity and accumulation phenomena. The reduction of the daily dose is an aspect of particular interest in the treatment of chronic diseases such as schizophrenia, which require prolonged eposure to the drug.
Formula (I) compounds can be administered over a dosage range generally varying from 0.02 to 200 mg/kg, depending upon the severity of the disease to be treated and its acute or chronic component. Doses outside the range indicated are, however, possible in particular conditions, under the supervision of a doctor.